Decitabine/cedazuridine
Decitabine/cedazuridine (oral fixed-dose combination) is approved in Europe for patients with newly diagnosed AML who are ineligible for standard induction chemotherapy. In a phase 3 study, decitabine/cedazuridine demonstrated pharmacokinetic equivalence to standard intravenous decitabine in AML patients not suitable for standard induction chemotherapy.[128]Geissler K, Koristek Z, Bernal Del Castillo T, et al. Oral Decitabine/cedazuridine vs intravenous decitabine for acute myeloid leukemia: final results of a randomized, crossover, registration-enabling, pharmacokinetics study. Blood 2023;142(suppl 1):1538.
Cladribine
A purine nucleoside analogue, one small phase 2 trial concluded that a cladribine-containing lower-intensity regimen was effective in older or unfit patients with newly diagnosed AML.[129]Kadia TM, Reville PK, Wang X, et al. Phase II study of venetoclax added to cladribine plus low-dose cytarabine alternating with 5-azacitidine in older patients with newly diagnosed acute myeloid leukemia. J Clin Oncol. 2022 Nov 20;40(33):3848-57.
https://ascopubs.org/doi/10.1200/JCO.21.02823
http://www.ncbi.nlm.nih.gov/pubmed/35704787?tool=bestpractice.com
In one phase 3 study, patients with untreated AML demonstrated improved survival with cladribine combined with standard induction therapy (daunorubicin and cytarabine) compared with those who received standard induction therapy alone.[130]Holowiecki J, Grosicki S, Giebel S, et al. Cladribine, but not fludarabine, added to daunorubicin and cytarabine during induction prolongs survival of patients with acute myeloid leukemia: a multicenter, randomized phase III study. J Clin Oncol. 2012 Jul 10;30(20):2441-8.
https://ascopubs.org/doi/10.1200/JCO.2011.37.1286
http://www.ncbi.nlm.nih.gov/pubmed/22508825?tool=bestpractice.com
Cladribine combined with standard induction therapy also improved survival in a phase 2 randomised trial of older patients (median age 66 years) with AML.[131]Pluta A, Robak T, Wrzesien-Kus A, et al. Addition of cladribine to the standard induction treatment improves outcomes in a subset of elderly acute myeloid leukemia patients. Results of a randomized Polish Adult Leukemia Group (PALG) phase II trial. Am J Hematol. 2017 Apr;92(4):359-66.
https://onlinelibrary.wiley.com/doi/10.1002/ajh.24654
http://www.ncbi.nlm.nih.gov/pubmed/28103640?tool=bestpractice.com
Phase 3 randomised controlled trials assessing the role of cladribine in the management of AML are continuing to recruit.[132]ClinicalTrials.gov. Cladribine; acute myeloid leukemia; phase 3 [internet publication].
https://clinicaltrials.gov/ct2/results?term=cladribine&cond=Acute+Myeloid+Leukemia&age_v=&gndr=&type=&rslt=&phase=2&Search=Apply
Sorafenib plus azacitidine for newly diagnosed or relapsed FLT3-mutated AML
Sorafenib is an oral kinase inhibitor. In one small phase 1/2 study (n=27) of patients with newly diagnosed FLT3-mutated AML who were unsuitable for standard chemotherapy, a response rate of 78% (26% with complete response) was achieved with sorafenib plus azacitidine.[133]Ohanian M, Garcia-Manero G, Levis M, et al. Sorafenib combined with 5-azacytidine in older patients with untreated FLT3-ITD mutated acute myeloid leukemia. Am J Hematol. 2018 Sep;93(9):1136-41.
https://onlinelibrary.wiley.com/doi/10.1002/ajh.25198
http://www.ncbi.nlm.nih.gov/pubmed/30028037?tool=bestpractice.com
In a phase 2 study of patients with relapsed FLT3-ITD mutated AML, a response rate of 46% (16% with complete response) was achieved with sorafenib plus azacitidine.[134]Ravandi F, Alattar ML, Grunwald MR, et al. Phase 2 study of azacytidine plus sorafenib in patients with acute myeloid leukemia and FLT-3 internal tandem duplication mutation. Blood. 2013 Jun 6;121(23):4655-62.
https://ashpublications.org/blood/article/121/23/4655/31475/Phase-2-study-of-azacytidine-plus-sorafenib-in
http://www.ncbi.nlm.nih.gov/pubmed/23613521?tool=bestpractice.com
Quizartinib for relapsed or refractory FLT3-mutated AML
Quizartinib is a potent oral kinase inhibitor. In an open-label phase 3 study of patients with relapsed or refractory FLT3-ITD-positive AML, quizartinib improved survival compared with salvage chemotherapy.[135]Cortes JE, Khaled S, Martinelli G, et al. Quizartinib versus salvage chemotherapy in relapsed or refractory FLT3-ITD acute myeloid leukaemia (QuANTUM-R): a multicentre, randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2019 Jul;20(7):984-97.
http://www.ncbi.nlm.nih.gov/pubmed/31175001?tool=bestpractice.com
Guadecitabine
Guadecitabine is a second-generation hypomethylating agent. It is formulated as a dinucleotide of the drug decitabine with deoxyguanosine, which increases the half-life of decitabine.[136]Saygin C, Carraway HE. Emerging therapies for acute myeloid leukemia. J Hematol Oncol. 2017 Apr 18;10(1):93.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5395764
http://www.ncbi.nlm.nih.gov/pubmed/28420416?tool=bestpractice.com
In a phase 3 study of patients with untreated AML who were unsuitable for intensive chemotherapy, guadecitabine did not demonstrate improved survival compared with a preselected treatment (e.g., azacitidine, decitabine, or low-dose cytarabine).[137]Roboz GJ, Döhner H, Gobbi M, et al. Results from a global randomized phase 3 study of guadecitabine (G) vs treatment choice (TC) in 815 patients with treatment naïve (TN) AML unfit for intensive chemotherapy (IC) ASTRAL-1 study: analysis by number of cycles. Blood 2019 Nov;134(1 suppl):2591. Clinical trials investigating its use in patients with relapsed or refractory AML are ongoing.[138]ClinicalTrials.gov. Guadecitabine; acute myeloid leukemia; phase 2 [internet publication].
https://clinicaltrials.gov/ct2/results?term=guadecitabine&cond=Acute+Myeloid+Leukemia&age_v=&gndr=&type=&rslt=&phase=1&Search=Apply
Clofarabine
Clofarabine is a second-generation purine nucleoside analogue. Findings from one study suggested that clofarabine with cytarabine during remission induction could potentially reduce the need for anthracycline and etoposide in paediatric patients with AML, and may reduce rates of cardiomyopathy and treatment-related cancer.[139]Rubnitz JE, Lacayo NJ, Inaba H, et al. Clofarabine can replace anthracyclines and etoposide in remission induction therapy for childhood acute myeloid leukemia: the AML08 multicenter, randomized phase III trial. J Clin Oncol. 2019 Aug 10;37(23):2072-81.
https://ascopubs.org/doi/10.1200/JCO.19.00327
http://www.ncbi.nlm.nih.gov/pubmed/31246522?tool=bestpractice.com
In a phase 3 study of older patients with AML who were unsuitable for intensive chemotherapy, clofarabine improved remission and overall response rates compared with low-dose cytarabine, but did not improve survival.[140]Burnett AK, Russell NH, Hunter AE, et al. Clofarabine doubles the response rate in older patients with acute myeloid leukemia but does not improve survival. Blood. 2013 Aug 22;122(8):1384-94.
https://ashpublications.org/blood/article/122/8/1384/32089/Clofarabine-doubles-the-response-rate-in-older
http://www.ncbi.nlm.nih.gov/pubmed/23838349?tool=bestpractice.com
Patients receiving clofarabine were at increased risk of myelotoxicity and required more supportive care.[140]Burnett AK, Russell NH, Hunter AE, et al. Clofarabine doubles the response rate in older patients with acute myeloid leukemia but does not improve survival. Blood. 2013 Aug 22;122(8):1384-94.
https://ashpublications.org/blood/article/122/8/1384/32089/Clofarabine-doubles-the-response-rate-in-older
http://www.ncbi.nlm.nih.gov/pubmed/23838349?tool=bestpractice.com
Crenolanib
Crenolanib is an oral benzimidazole type I tyrosine kinase inhibitor. It selectively and potently inhibits signalling of wild-type and mutant isoforms of class III receptor tyrosine kinases FLT3 and PDGFR-alpha/beta. Crenolanib is currently being evaluated in phase 3 studies of adult patients with FLT3-mutated AML.[141]ClinicalTrials.gov. Crenolanib; acute myeloid leukemia; phase 3 [internet publication].
https://clinicaltrials.gov/ct2/results?term=crenolanib&cond=Acute+Myeloid+Leukemia&age_v=&gndr=&type=&rslt=&phase=2&Search=Apply
The EMA has granted orphan drug designation to crenolanib for the treatment of AML.
Flotetuzumab
Flotetuzumab is a dual-affinity re-targeting (DART) antibody-based molecule that recognises CD123 with CD3. The primary mechanism of action of flotetuzumab is believed to be its ability to redirect T lymphocytes to kill CD123-expressing cells. Leukaemic stem cells are characterised by high levels of CD123 expression. Flotetuzumab is currently being evaluated in phase 1/2 studies of patients with relapsed or refractory AML.[142]ClinicalTrials.gov. Flotetuzumab; acute myeloid leukemia; phase 2 [internet publication].
https://clinicaltrials.gov/ct2/results?term=flotetuzumab&cond=Acute+Myeloid+Leukemia&age_v=&gndr=&type=&rslt=&phase=1&Search=Apply
The FDA has granted orphan drug status to flotetuzumab.
Gilteritinib plus venetoclax and azacitidine
In a phase 1/2 study, the addition of gilteritinib (an oral kinase inhibitor) to venetoclax plus azacitidine resulted in a high rate of complete remission/complete remission with incomplete haematological recovery (96%) and a deep FLT3 molecular response in patients with newly diagnosed FLT3-mutated AML.[143]Short NJ, Daver N, Dinardo CD, et al. Azacitidine, venetoclax, and gilteritinib in newly diagnosed and relapsed or refractory FLT3-mutated AML. J Clin Oncol. 2024 May 1;42(13):1499-1508.
http://www.ncbi.nlm.nih.gov/pubmed/38277619?tool=bestpractice.com